This project builds upon an existing program that has already generated exciting results with a novel vaccine, based on multiple peptides derived from the V3 domain of gp120 conjugated to PPD. Most notably, we observed in animals the generation of high titered primary isolate neutralizing antibodies and in HIV + vaccines major reduction in plasma HIV levels that were correlated with substantial increases in titers of neutralizing against V3 loop epitopes. This system utilizes the potent adjuvanticity of PPD in BCG-preimmunized subjects and animals. Based on these observations it appears that this vaccine has demonstrated more effectiveness than any other HIV vaccine for which data have been reported. We believe that despite difficulties in generating effective antibodies against env regions in the past, these domains are in fact the major neutralizing target in vivo. We now propose to expand this approach to 1) develop improved V3 peptide and gp41 vaccine conjugates focusing on PPD and various recombinant proteins of M. tuberculosis, 2) evaluate hypothesis for the mechanisms of action of PDD as a unique vaccine carrier to allow for improvement of conjugate immunogenicity. 3) Test the utility of V3 loop and gp41 peptide cocktail vaccines in the prevention of HIV infection in animal models, including transgenic hu CD4/CCR5 mice, SCID-hu mice, HIV+ chimpanzees and in limited clinical trials in HIV seronegative and HIV + volunteers. We believe that this is a feasible approach towards the development of effective HIV vaccines for preventative and therapeutic purposes. Since our preliminary vaccine has already shown efficacy in a small scale human clinical trials, additional experiments with this vaccine can be done now. Moreover, the hypothesized improvements to the vaccine realistically can be incorporated into the vaccine within a short time.